Fundamental advances in genetic sequencing technologies were stimulated by the human genome project and are now in turn transforming genome science and medicine. Yet the promise of genomic medicine remains limited by the lack of definitive sources of information about the genetic contributions to disease. Although many groups are attempting to address this gap individually, such efforts will ultimately fall shor if they remain disconnected. The Clinically Relevant Variants Resource represents a collaborative effort of the genetics community to establish an evidence-based resource for the assessment of the clinical relevance of genes and variants. This knowledge base is critical for confident, efficient analysis and interpretation of genome-scale sequence data. The objective is to provide a publicly available consensus summary of the evidence from the medical literature, basic science researchers, and clinical laboratories regarding the genes and variants that are implicated in human health and disease. Dedicated portals will be provided for researchers, clinical laboratories, physicians, patients, and electronic health records to ensure that the resource is widely accessible. The consortium of investigators will accomplish this objective by pursuing five specific aims: 1) developing a semi-quantitative methodology for assessing the clinical actionability of gene- phenotype pairs, which will allow stakeholder groups to provide guidance on the reporting and use of such genetic results; 2) establishing a standardized process for evaluating whether variants are benign, related to disease, or of uncertain significance; 3) deploying an informatics infrastructure to support the activities of the consortiu by aggregating information from disparate sources and presenting it for human evaluation; 4) assembling clinical domain-specific working groups to systematically evaluate the genes (and the variants in those genes) that are clinically relevant; and 5) ensuring the interoperability of he resource with electronic medical record systems. The approach innovates by developing novel approaches for the assessment of genes and variants that are robust and reproducible, and by establishing a distributed informatics system for aggregating and displaying information, with mechanisms for updating and reanalysis. The proposal is forward-thinking in that attention will be paid to ensuring the interoperability of the resource with diverse end-users, including electronic health records. The proposed resource project is significant because it will provide freely available expert curation of the human genome across a substantial number of clinical domains, with a transparent and evidence-based approach.